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1.
Front Neurol ; 15: 1352779, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38689876

RESUMO

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder of the central nervous system characterized by recurrent, disabling attacks that affect the optic nerve, spinal cord, and brain/brainstem. While rituximab, targeting CD20-positive B-cells, is used as an off-label therapy for NMOSD, some patients continue to exhibit breakthrough attacks and/or adverse reactions. Inebilizumab, a humanized and glycoengineered monoclonal antibody targeting CD19-positive B-cells, has been FDA approved for the treatment of NMOSD in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. Given the limited real-world data on the efficacy and safety of inebilizumab, especially in those transitioning from rituximab, a retrospective chart review was conducted on 14 NMOSD patients from seven centers. Of these, 71.4% (n = 10) experienced a combined 17 attacks during rituximab treatment, attributed to either breakthrough disease (n = 10) or treatment delay (n = 7). The mean duration of rituximab treatment was 38.4 months (3.2 years). Notably, no subsequent attacks were observed during inebilizumab treatment [mean duration of inebilizumab treatment was 19.3 months (1.6 years)], underscoring its potential as an effective treatment for NMOSD. Our data suggest that inebilizumab provides clinical benefit with effective disease control and a favorable safety profile for patients transitioning from rituximab.

2.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200201, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38285968

RESUMO

A 42-year-old woman and active cocaine user complained of subacutely worsening blurred vision and imbalance. Examination of the brain MRI showed rapidly expanding white matter lesions. Brain biopsy was consistent with inflammatory demyelination. Given an unusual presentation and a history of cocaine use, a broad differential diagnosis was considered including neurologic toxidromes.


Assuntos
Cocaína , Esclerose Múltipla , Substância Branca , Feminino , Humanos , Adulto , Esclerose Múltipla/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Imageamento por Ressonância Magnética , Neuroimagem
3.
Neurol Clin Pract ; 14(1): e200222, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38148835

RESUMO

Background and Objectives: Multiple sclerosis (MS) commonly affects women in their childbearing years, necessitating discussion between patients and their MS treatment team around the issues of family planning, pregnancy, and postpartum experiences. This study assessed the impact of a diagnosis of MS on women's reproductive decision-making and on their perception of counseling received surrounding pregnancy. It also sought to evaluate trends in pregnancy and postpartum experiences and determine whether experiences differed by race, ethnicity, and zip code. Methods: Women with an MS diagnosis seen at the University of Virginia MS Clinic or at Virginia Commonwealth University (VCU) MS Clinic were invited to participate in a survey study. MS disease and pregnancy history, and, when appropriate, reasons for pregnancy avoidance were collected. Respondents who had >1 pregnancy following MS diagnosis were asked to evaluate the counseling they received from medical professionals and to share their pregnancy experiences including complications during pregnancy, delivery outcomes, and postpartum experience including breastfeeding. Results: Of the 280 respondents, 76.6% were currently receiving MS specialty care. Most of them (79.3%) had not been pregnant following MS diagnosis. Of them, 20.1% indicated that this decision was driven by MS-related concerns: MS worsening with pregnancy (47%); ability to care for child secondary to MS (35%); passing MS onto child (19%); stopping disease-modifying therapies to attempt pregnancy (14%); lack of knowledge about options for pregnancy and MS (9%). Women with a more recent estimated decade of pregnancy were more likely to report neurologist counseling regarding MS and pregnancy (pregnancy before 2000: 40%, 2000-2010: 64.7%, 2010- present: 83.3%; χ2 0.020). Breastfeeding initiation was reported in 71.4% of postdiagnosis pregnancies (median duration 6 months, interquartile range 1.75-11). Discussion: Over the past few decades, women with MS have received a wide range of evolving guidance surrounding family planning, pregnancy, and postpartum care. Survey data suggest improvements in MS/pregnancy counseling and medical management in recent years, which may be driven by an increase in research in the field. There remains an important need and opportunity to improve counseling of women with MS who are considering pregnancy.

4.
Front Neurol ; 14: 1259413, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37859654

RESUMO

Background: Multiple Sclerosis (MS) disease progression has notable heterogeneity among patients and over time. There is no available single method to predict the risk of progression, which represents a significant and unmet need in MS. Methods: MS and healthy control (HC) participants were recruited for a 2-year observational study. A latent-variable growth mixture model (GMM) was applied to cluster baseline 6-min walk gait speed trajectories (6MWGST). MS patients within different 6 MWGST clusters were identified and stratified. The group membership of these MS patients was compared against 2-year confirmed-disease progression (CDP). Clinical and patient-reported outcome (PRO) measures were compared between HC and MS subgroups over 2 years. Results: 62 MS and 41 HC participants completed the 2-year study. Within the MS cohort, 90% were relapsing MS. Two distinct patterns of baseline 6 MWGST emerged, with one cluster displaying a faster gait speed and a typical "U" shape, and the other showing a slower gait speed and a "flattened" 6 MWGST curve. We stratified MS participants in each cluster as low- and high-risk progressors (LRP and HRP, respectively). When compared against 2-year CDP, our 6 MWGST approach had 71% accuracy and 60% positive predictive value. Compared to the LRP group, those MS participants stratified as HRP (15 out of 62 MS participants), were on average 3.8 years older, had longer MS disease duration and poorer baseline performance on clinical outcomes and PROs scores. Over the subsequent 2 years, only the HRP subgroup showed a significant worsened performance on 6 MW, clinical measures and PROs from baseline. Conclusion: Baseline 6 MWGST was useful for stratifying MS participants with high or low risks for progression over the subsequent 2 years. Findings represent the first reported single measure to predict MS disease progression with important potential applications in both clinical trials and care in MS.

5.
Mult Scler Relat Disord ; 73: 104670, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36996634

RESUMO

BACKGROUND: Ketogenic diets have anti-inflammatory and neuroprotective properties which make these diets an attractive complimentary treatment approach for patients living with multiple sclerosis (MS). The objective of this study was to assess the impact of ketogenic diets on neurofilament light chain (NfL), a biomarker of neuroaxonal injury. METHODS: Thirty-nine subjects with relapsing MS completed a 6-month ketogenic diet intervention. NfL levels were assayed at both baseline (pre-diet) and 6-months on-diet. In addition, ketogenic diet study participants were compared to a cohort (n = 31) of historical, untreated MS controls. RESULTS: Baseline (pre-diet) mean NfL was 5.45 pg/ml (95% CI 4.59 - 6.31). After 6 months on ketogenic diet, mean NfL was not significantly changed (5.49 pg/ml; 95% CI 4.82 - 6.19). Compared to untreated MS controls (mean 15.17 pg/ml), NfL levels for the ketogenic diet cohort were relatively low. MS subjects with higher levels of ketosis (as measured by serum beta-hydroxybutyrate) exhibited greater reductions in NfL between baseline and 6-months on ketogenic diet. CONCLUSIONS: Ketogenic diets do not worsen biomarkers of neurodegeneration in relapsing MS patients, with stable, low levels of NfL observed throughout the diet intervention. Subjects with greater biomarkers of ketosis experienced a higher degree of improvement in serum NfL. CLINICAL TRIAL IDENTIFIER: NCT03718247 - "Utilization of the Ketogenic Diet in Patients with Relapsing-Remitting MS" https://clinicaltrials.gov/ct2/show/NCT03718247.


Assuntos
Dieta Cetogênica , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Filamentos Intermediários , Biomarcadores
6.
Handb Clin Neurol ; 175: 235-259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33008528

RESUMO

Neuroinflammation is implicated in contributing to a variety of neurologic and somatic illnesses including Alzheimer's disease (AD), Parkinson's disease (PD), and depression. In this chapter, we focus on the role of neuroinflammation in mediating these three illnesses and portray interactions between the immune response and the central nervous system in the context of sex differences in disease progression. The majority of this chapter is supported by clinical findings; however, we occasionally utilize preclinical models where human studies are currently lacking. We begin by detailing the pathology of neuroinflammation, distinguishing between acute and chronic inflammation, and examining contributions from the innate and adaptive immune systems. Next, we summarize potential mechanisms of immune cell mediators including interleukin-1 beta (IL-1ß), tumor necrosis factor α, and IL-6 in AD, PD, and depression development. Given the strong sex bias seen in these illnesses, we additionally examine the role of sex hormones, e.g., estrogen and testosterone in mediating neuroinflammation at the cellular level. Systematically, we detail how sex hormones may contribute to distinct behavioral and clinical symptoms and prognosis between males and females with AD, PD, or depression. Finally, we highlight the possible role of exercise in alleviating neuroinflammation, as well as evidence that antiinflammatory drug therapies improve cognitive symptoms observed in brain-related diseases.


Assuntos
Doença de Alzheimer , Doença de Parkinson , Exercício Físico , Feminino , Humanos , Sistema Imunitário , Inflamação , Masculino
7.
J Med Chem ; 63(20): 11819-11830, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32945676

RESUMO

Mitochondrial dysfunction has been recognized as an essential contributor to many human diseases including neurodegenerative disorders. However, the exact pathological role of mitochondrial dysfunction, especially in mitochondrial reactive oxygen species-associated oxidative stress, remains elusive, partially due to the lack of chemical probes with well-defined mechanisms of action. Herein, we describe the characterization and discovery of a rationally designed small molecule ZCM-I-1 as a selective modulator of the production of reactive oxygen species from mitochondrial complex I that does not alter mitochondrial membrane potential and bioenergetics. Chemical biology studies employing photoaffinity probes derived from ZCM-I-1 demonstrated its novel mechanism of action of modulating complex I via interactions with the flavin mononucleotide site, proximal in the reaction pathway within complex I.


Assuntos
Descoberta de Drogas , Complexo I de Transporte de Elétrons/metabolismo , Indóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Camundongos , Mitocôndrias/metabolismo , Modelos Moleculares , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
8.
PLoS One ; 15(6): e0235110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584865

RESUMO

Programmed axonal degeneration, also known as Wallerian degeneration, occurs in immune-mediated central nervous system (CNS) inflammatory disorders such as multiple sclerosis and the animal model experimental allergic encephalomyelitis (EAE). Sterile alpha and TIR domain containing protein 1 (SARM1) functions to promote programmed axonal degeneration. To test the hypothesis that loss of SARM1 will reduce axonal degeneration in immune-mediated CNS inflammatory disorders, the course and pathology of EAE was compared in Sarm1 knockout mice and wild type littermates. The clinical course of EAE was similar in Sarm1 knockout and wild type. Analysis of EAE in mice expressing neuronal yellow fluorescent protein (YFP) showed significantly less axonal degeneration in Sarm1 knockout mice compared to wild type littermates at 14 days post-induction of EAE. At 21 days post-induction, however, difference in axonal degeneration was not significant. At 42 days post-induction, Sarm1 knockout mice were indistinguishable from wild type with respect to markers of axonal injury, and were similar with respect to axonal density in the lumbar cords. There was no significant change in peripheral immune activation or CNS inflammatory cell infiltration associated with EAE in Sarm1 knockout mice. In conclusion, Sarm1 deletion delayed axonal degeneration early in the course of CNS inflammation, but did not confer long-term protection from axonal degeneration in an animal model of immune-mediated CNS inflammation.


Assuntos
Proteínas do Domínio Armadillo , Axônios , Proteínas do Citoesqueleto , Encefalomielite Autoimune Experimental , Técnicas de Inativação de Genes , Medula Espinal , Animais , Proteínas do Domínio Armadillo/genética , Proteínas do Domínio Armadillo/metabolismo , Axônios/metabolismo , Axônios/patologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Camundongos , Camundongos Knockout , Medula Espinal/metabolismo , Medula Espinal/patologia , Fatores de Tempo
9.
Mult Scler Relat Disord ; 39: 101924, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31927153

RESUMO

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an autoimmune neurological disorder associated with the presence of anti-GFAP IgG. Meningoencephalitis is the predominant clinical presentation of autoimmune GFAP astrocytopathy in published case series. We report a case of autoimmune GFAP astrocytopathy with the unusual feature of radiculoneuritis in addition to encephalomyelitis, resulting in flaccid paralysis unresponsive to immunotherapy. Imaging data confirmed involvement of brain, spinal cord and nerve roots. Electrodiagnostic testing showed changes consistent with a severe sensorimotor neuropathy with active denervation. The results of this case suggest the need for future studies to assess the impact of peripheral nerve involvement on the outcome of autoimmune GFAP astrocytopathy.

10.
J Neuroimmunol ; 339: 577118, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790981

RESUMO

Cyclophilin A has multiple known functions in inflammation. Intracellular cyclophilin A modulates T helper 2 response (Th2) and extracellular cyclophilin A functions as a leukocyte chemotactic factor. The contribution of cyclophilin A to central nervous system (CNS) inflammation has not been reported. To test the hypothesis that inhibition of cyclophilin A would ameliorate immune-mediated CNS inflammation, we compared the course and neuroimmunology of experimental allergic encephalomyelitis (EAE) in cyclophilin A knockout mice and wild type littermates. There was a trend towards lower incidence of EAE in cyclophilin A knockout mice, but the clinical course of EAE among animals that manifested clinical signs of EAE was similar in cyclophilin A knockout and wild type littermates. Antigen recall response to myelin oligodendrocyte glycoprotein (MOG) peptide showed that interferon-γ release was lower in cyclophilin A knockout mice. Analysis of CNS inflammatory cells showed that CD3+ T cell infiltration into the CNS was lower in cyclophilin A knockout mice. These results showed that the loss of cyclophilin A results in altered peripheral immune activation and CNS leukocyte infiltration, but these changes did not result in a substantial change in the clinical course of EAE.


Assuntos
Ciclofilina A/deficiência , Encefalomielite Autoimune Experimental/metabolismo , Imunidade Celular/fisiologia , Animais , Ciclofilina A/genética , Ciclofilina A/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Ann Clin Transl Neurol ; 6(8): 1383-1394, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31402625

RESUMO

OBJECTIVE: Human T cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8+ T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV-1-specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL-2 and IL-15 stimulate memory CD8+ T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu-Mikß1, a humanized monoclonal antibody directed toward the IL-2/IL-15 receptor ß-chain (IL-2/IL-15Rß: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL-15 action. METHODS: Hu-Mikß1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu-Mikß1 were administered at 3-week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV-1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients. RESULTS: There was no significant toxicity associated with Hu-Mikß1 administration in HAM/TSP patients. Saturation of CD122 by Hu-Mikß1 was achieved in five out of nine HAM/TSP patients. Administration of Hu-Mikß1 was associated with inhibition of aberrant CD8+ T cell function including spontaneous lymphoproliferation and degranulation and IFN-γ expression, especially in HAM/TSP patients that achieved CD122 saturation. INTERPRETATION: The treatment with Hu-Mikß1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose-related toxicity.


Assuntos
Anticorpos Monoclonais/farmacologia , Subunidade beta de Receptor de Interleucina-2/antagonistas & inibidores , Paraparesia Espástica Tropical/imunologia , Paraparesia Espástica Tropical/terapia , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Citocinas/biossíntese , Feminino , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Humanos , Interferon gama/metabolismo , Interleucina-15 , Interleucina-2 , Subunidade beta de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso , Linfócitos T Citotóxicos/imunologia
12.
Cancers (Basel) ; 11(1)2018 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-30602670

RESUMO

The recent progresses in understanding of cancer glycolytic phenotype have offered new strategies to manage ovarian cancer and other malignancies. However, therapeutic targeting of glycolysis to treat cancer remains unsuccessful due to complex mechanisms of tumor glycolysis and the lack of selective, potent and safe glycolytic inhibitors. Recently, BAY-876 was identified as a new-generation inhibitor of glucose transporter 1 (GLUT1), a GLUT isoform commonly overexpressed but functionally poorly defined in ovarian cancer. Notably, BAY-876 has not been evaluated in any cell or preclinical animal models since its discovery. We herein took advantage of BAY-876 and molecular approaches to study GLUT1 regulation, targetability, and functional relevance to cancer glycolysis. The anti-tumor activity of BAY-876 was evaluated with ovarian cancer cell line- and patient-derived xenograft (PDX) models. Our results show that inhibition of GLUT1 is sufficient to block basal and stress-regulated glycolysis, and anchorage-dependent and independent growth of ovarian cancer cells. BAY-876 dramatically inhibits tumorigenicity of both cell line-derived xenografts and PDXs. These studies provide direct evidence that GLUT1 is causally linked to the glycolytic phenotype in ovarian cancer. BAY-876 is a potent blocker of GLUT1 activity, glycolytic metabolism and ovarian cancer growth, holding promise as a novel glycolysis-targeted anti-cancer agent.

13.
J Biol Chem ; 292(51): 20989-20997, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29046352

RESUMO

Dineolignans manassantin A and B from the plant Saururus cernuus are used in traditional medicine to manage a wide range of ailments such as edema, jaundice, and gonorrhea. Cell-based studies have identified several molecular target candidates of manassantin including NF-κB, MAPK, STAT3, and hypoxia-inducible factor 1α (HIF-1α). It is unclear whether or how these structurally diverse proteins or pathways mediate any of the medical benefits of manassantin in vivo Moreover, it has recently been reported that manassantin causes developmental arrest in zebrafish by inhibiting the mitochondrial complex I, but it is unknown whether manassantin inhibits mitochondrial respiration in intact mammalian cells and live animals. Here, we present direct evidence that manassantin potently and specifically inhibits the mitochondrial complex I and bioenergetic activity in mammalian systems. Manassantin had no effect on complex II- or complex IV-mediated respiration. Of note, it decreased NADH-ubiquinone reductase activity but not the activity of NADH-ferricyanide reductase. Treatment with manassantin reduced cellular ATP levels and concomitantly stimulated AMP-activated protein kinase in vitro and in vivo As an adaptive response to manassantin-induced bioenergetic deficiency, mammalian cells up-regulated aerobic glycolysis, a process mediated by AMP-activated protein kinase (AMPK) independently of HIF-1α. Together these results demonstrate a biologically important activity of manassantin in the control of complex I-mediated respiration and its profound effects on oxygen utilization, energy homeostasis, and glucose metabolism in mammalian cells.


Assuntos
Complexo I de Transporte de Elétrons/antagonistas & inibidores , Metabolismo Energético/efeitos dos fármacos , Furanos/farmacologia , Lignanas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos
14.
J Neuroimmunol ; 311: 40-48, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28789840

RESUMO

Cyclophilins have diverse functions that may affect the course of central nervous system (CNS) inflammatory disorders. Anti-inflammatory and neuroprotective mechanisms may be targeted by inhibition of cyclophilin A-dependent and cyclophilin D-dependent functions, respectively. We tested the effect of cyclophilin inhibition on CNS inflammation by administering N-methyl-4-isoleucine-cyclosporin (NIM811) to mice undergoing experimental allergic encephalomyelitis (EAE). Treatment with NIM811 resulted in significant reduction of EAE clinical severity. Analysis of mitochondrial calcium retention capacity and the course of EAE in cyclophilin D knockout mice indicated that the effect of NIM811 on EAE was not entirely cyclophilin D-dependent. NIM811-treated EAE animals showed reduction in interleukin-2 expression and reduction in CNS inflammatory infiltrates. These results indicate that anti-inflammatory rather than neuroprotective mechanisms associated with cyclophilins are likely involved in the mechanism of NIM811 in EAE.


Assuntos
Ciclosporina/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunossupressores/uso terapêutico , Animais , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Calcineurina/metabolismo , Cálcio/metabolismo , Peptidil-Prolil Isomerase F , Ciclofilinas/deficiência , Ciclofilinas/genética , Ciclosporina/metabolismo , Ciclosporina/farmacologia , Citocinas/genética , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Imunossupressores/farmacologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Baço/metabolismo , Baço/ultraestrutura , Fatores de Tempo
15.
J Neuroimmunol ; 304: 43-50, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-27769524

RESUMO

Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TSP) is believed to be the result of "bystander damage" involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI-CaFé), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to-cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell-cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after 18h of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system.


Assuntos
Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Leucócitos Mononucleares/metabolismo , Paraparesia Espástica Tropical/metabolismo , Fagócitos/metabolismo , Células Cultivadas , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/metabolismo , Paraparesia Espástica Tropical/imunologia , Fagócitos/imunologia
16.
Glia ; 64(7): 1190-209, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27100937

RESUMO

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone-induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE-induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology. GLIA 2016;64:1190-1209.


Assuntos
Segmento Inicial do Axônio/fisiologia , Axônios/patologia , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica/fisiologia , Microglia/metabolismo , Animais , Animais Geneticamente Modificados , Doenças Autoimunes do Sistema Nervoso/induzido quimicamente , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Doenças Autoimunes do Sistema Nervoso/patologia , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Morte Celular/fisiologia , Células Cultivadas , Cuprizona/toxicidade , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácidos Hidroxâmicos/uso terapêutico , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Inibidores da Monoaminoxidase/toxicidade , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
J Neuroinflammation ; 12: 27, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25889344

RESUMO

BACKGROUND: The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis. METHODS: The effect of LXR activation on microglia and central nervous system (CNS) inflammation was studied using a synthetic LXR agonist in cultured microglia, a microglial cell line and experimental allergic encephalomyelitis (EAE), an animal model of CNS inflammation. RESULTS: LXR activation inhibited nitric oxide synthase 2, inducible (Nos2) expression and nitric oxide production in lipopolysaccharide (LPS)-stimulated microglia. Inhibition of microglial activation in response to interferon-γ was less reliable. In LPS-stimulated cells, LXR activation did not inhibit nuclear translocation of NF-kappaB1 p50. Instead, LXR-dependent Nos2 repression was associated with inhibition of histone 4 acetylation and inhibition of NF-kappaB1 p50 binding at the Nos2 promoter. Histone acetylation and NF-kappaB1 p50 binding were mechanistically linked, and histone deacetylase (HDAC) activity appeared to be important for LXR-dependent transcriptional repression of Nos2. Analysis of CNS gene expression in animals undergoing EAE showed that the expressions of Lxr and LXR-dependent genes were downregulated during CNS inflammation. Nevertheless, administration of LXR agonist GW3965 during the effector phase of EAE delayed the onset of clinical disease and reversed the diminished expression of LXR-dependent reverse cholesterol transport genes. However, the CNS expressions of Nos2 and other inflammatory genes were not significantly inhibited by LXR activation in EAE, and clinical disease severity was comparable to vehicle controls at later time points in LXR agonist treated animals. CONCLUSIONS: LXR can be targeted to modulate microglial activation. LXR-dependent repression of inflammatory genes may be stimulus-dependent and impaired by HDAC inhibition. Endogenous LXR activity does not appear to modulate CNS inflammation, but LXR activity can be partially restored in the CNS by administration of exogenous LXR agonist with an impact on clinical disease severity at early, but not late, time points in EAE.


Assuntos
Citocinas/metabolismo , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores Nucleares Órfãos/metabolismo , Animais , Animais Recém-Nascidos , Benzoatos/uso terapêutico , Benzilaminas/uso terapêutico , Células Cultivadas , Imunoprecipitação da Cromatina , Desoxirribonucleases/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Perfilação da Expressão Gênica , Histonas/metabolismo , Lipopolissacarídeos/farmacologia , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Receptores Nucleares Órfãos/antagonistas & inibidores , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Ligação Proteica/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
18.
Glia ; 63(3): 423-40, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25331559

RESUMO

Redox-signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF-κB p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro-inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H2 O2 showed altered NF-κB p50 protein-protein interactions, decreased NF-κB p50 DNA binding, and augmented late-stage TNFα expression, indicating that H2 O2 impairs NF-κB p50 function and prolongs amplified M1 activation. NF-κB p50(-/-) mice and cultures exhibited a disrupted M2 (alternative) response and impaired resolution of the M1 response. Persistent neuroinflammation continued 1 week after LPS (1 mg/kg, IP) administration in the NF-κB p50(-/-) mice. However, peripheral inflammation had already resolved in both strains of mice. Treatment with the spin-trap DMPO mildly reduced LPS-induced 22 h TNFα in the brain in NF-κB p50(+/+) mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFα production in NF-κB p50(-/-) mice, implicating a fundamental role for NF-κB p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-κB p50 as a key redox-signaling mechanism regulating the M1/M2 balance in microglia, where loss of function leads to a CNS-specific vulnerability to chronic inflammation.


Assuntos
Peróxido de Hidrogênio/metabolismo , Microglia/fisiologia , Subunidade p50 de NF-kappa B/metabolismo , Animais , Encéfalo/imunologia , Linhagem Celular , Células Cultivadas , DNA/metabolismo , Modelos Animais de Doenças , Inflamação/fisiopatologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidade p50 de NF-kappa B/genética , Neuroimunomodulação/fisiologia , Oxirredução , Ratos , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Mult Scler Int ; 2014: 686045, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24860668

RESUMO

Background. In multiple sclerosis (MS), symptom management and improved health-related quality of life (HrQOL) may be modified by smoking. Objective. To evaluate the extent to which smoking is associated with worsened health outcomes and HrQOL for postmenopausal women with MS. Methods. We identified 251 Women's Health Initiative Observational Study participants with a self-reported MS diagnosis. Using a linear model, we estimated changes from baseline to 3 years for activities of daily living, total metabolic equivalent tasks (MET) hours per week, mental and physical component scales (MCS, PCS) of the SF-36, and menopausal symptoms adjusting for years since menopause and other confounders. Results. Nine percent were current and 50% past smokers. Age at smoking initiation was associated with significant changes in MCS during menopause. PCS scores were unchanged. While women who had ever smoked experienced an increase in physical activity during menopause, the physical activity levels of women who never smoked declined. Residual confounding may explain this finding. Smoking was not associated with change in menopausal symptoms during the 3-year follow-up. Conclusion. Smoking was not associated with health outcomes among post-menopausal women with MS.

20.
J Neuroimmune Pharmacol ; 9(4): 522-32, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24845974

RESUMO

HTLV-1 is a human retrovirus that is associated with the neuroinflammatory disorder HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). In these patients, HTLV-1 is primarily found in the CD4(+)CD25(+) T cell subset (Regulatory T cells:Tregs), which is responsible for peripheral immune tolerance and is known to be dysfunctional in HAM/TSP. Recent evidence suggests that FoxP3 expression and function is determined epigenetically through DNA demethylation in the Treg-specific demethylated region (TSDR). We analyzed the methylation of the TSDR in PBMCs, CD4(+) T cells, and CD4(+)CD25(+) T cells from normal healthy donors (NDs) and HAM/TSP patients. We demonstrated that there is decreased demethylation in analyzed PBMCs and CD4(+)CD25(+) T cells from HAM/TSP patients as compared to NDs. Furthermore, decreased TSDR demethylation was associated with decreased functional suppression by Tregs. Additionally, increased HTLV-1 Tax expression in HAM/TSP PBMC culture correlated with a concomitant decline in FoxP3 TSDR demethylation. Overall, we suggest that HTLV-1 infection decreases Treg functional suppressive capacity in HAM/TSP through modification of FoxP3 TSDR demethylation and that dysregulated Treg function may contribute to HAM/TSP disease pathogenesis.


Assuntos
Metilação de DNA , Epigênese Genética , Fatores de Transcrição Forkhead/metabolismo , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/metabolismo , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Feminino , Produtos do Gene tax/biossíntese , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
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